1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Further information on research design is available in the Nature
Portfolio Reporting Summary linked to this article.
Data availability
The data generated in this study are available in the Genomic Expression Archive (GEA) database under the accession numbers E-GEAD-561
for bulk RNA-seq [https://ddbj.nig.ac.jp/public/ddbj_database/gea/
experiment/E-GEAD-000/E-GEAD-561/] and E-GEAD-562 for scRNAseq data [https://ddbj.nig.ac.jp/public/ddbj_database/gea/experiment
/E-GEAD-000/E-GEAD-562/]. Data for TCGA-COREAD was accessed
through cBioportal (https://www.cbioportal.org). Raw gene expression data of CRC patient dataset (GSE35602, GSE14333 and GSE17536)
were directly accessed through the GEO website (NCBI). Raw gene
expression (count) data and metadata of single cell transcriptomic
dataset of human CRCs (SMC) were directly accessed through the GEO
website (GSE132465), and converted into Seurat object. Published
single cell transcriptome data of orthotopic MTO tumor was downloaded from GEO website (GSE154863), and converted into Seurat
object. The remaining data are available in the Article, Supplementary
Information or Source Data file. Source data are provided with
this paper.
Nature Communications | (2023)14:5534
16.
17.
18.
19.
20.
21.
Martinez-Ordoñez, A. et al. Hyaluronan driven by epithelial aPKC
deficiency remodels the microenvironment and creates a vulnerability in mesenchymal colorectal cancer. Cancer Cell 41,
252–271.e259 (2023).
Calon, A. et al. Stromal gene expression defines poor-prognosis
subtypes in colorectal cancer. Nat. Genet. 47, 320–329 (2015).
Nakanishi, Y. et al. Simultaneous loss of both atypical protein kinase
C genes in the intestinal epithelium drives serrated intestinal cancer
by impairing immunosurveillance. Immunity 49, 1132–1147.e1137
(2018).
Kasashima, H. et al. Stromal SOX2 upregulation promotes tumorigenesis through the generation of a SFRP1/2-expressing cancerassociated fibroblast population. Dev. Cell 56, 95–110.e110
(2021).
Guinney, J. et al. The consensus molecular subtypes of colorectal
cancer. Nat. Med. 21, 1350–1356 (2015).
Becht, E. et al. Immune and stromal classification of colorectal
cancer is associated with molecular subtypes and relevant for
precision immunotherapy. Clin. Cancer Res. 22, 4057–4066
(2016).
De Sousa, E. et al. Poor-prognosis colon cancer is defined by a
molecularly distinct subtype and develops from serrated precursor
lesions. Nat. Med. 19, 614–618 (2013).
Goswami, S., Anandhan, S., Raychaudhuri, D. & Sharma, P. Myeloid
cell-targeted therapies for solid tumours. Nat. Rev. Immunol.
(2022).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Kalluri, R. The biology and function of fibroblasts in cancer. Nat.
Rev. Cancer 16, 582–598 (2016).
Sweetwyne, M. T. & Murphy-Ullrich, J. E. Thrombospondin1 in tissue
repair and fibrosis: TGF-β-dependent and independent mechanisms. Matrix Biol. 31, 178–186 (2012).
Ramchandani, D. & Mittal, V. Thrombospondin in Tumor Microenvironment. Adv. Exp. Med. Biol. 1272, 133–147 (2020).
Markovic, S. N. et al. A phase II study of ABT-510 (thrombospondin-1
analog) for the treatment of metastatic melanoma. Am J Clin Oncol
30, 303–309 (2007).
Ebbinghaus, S. et al. Phase 2 study of ABT-510 in patients with
previously untreated advanced renal cell carcinoma. Clin. Cancer
Res. 13, 6689–6695 (2007).
Baker, L. H. et al. Randomized, phase II study of the
thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 in
patients with advanced soft tissue sarcoma. J. Clin. Oncol. 26,
5583–5588 (2008).
Joanito, I. et al. Single-cell and bulk transcriptome sequencing
identifies two epithelial tumor cell states and refines the consensus
molecular classification of colorectal cancer. Nat. Genet. 54,
963–975 (2022).
Tauriello, D. V. F. et al. TGFβ drives immune evasion in genetically
reconstituted colon cancer metastasis. Nature 554,
538–543 (2018).
Zhao, Y. et al. Thrombospondin-1 triggers macrophage IL-10 production and promotes resolution of experimental lung injury.
Mucosal. Immunol. 7, 440–448 (2014).
Connolly, K. A. et al. A reservoir of stem-like CD8. Sci. Immunol. 6,
eabg7836 (2021).
Li, H. et al. Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma. Cell 176,
775–789.e718 (2019).
Krishna, S. et al. Stem-like CD8 T cells mediate response of adoptive
cell immunotherapy against human cancer. Science 370,
1328–1334 (2020).
17
Article
22. Li, Z., He, L., Wilson, K. & Roberts, D. Thrombospondin-1 inhibits
TCR-mediated T lymphocyte early activation. J. Immunol. 166,
2427–2436 (2001).
23. Sato, T. et al. Reciprocal control of G1-phase progression is required
for Th-POK/Runx3-mediated CD4/8 thymocyte cell fate decision. J.
Immunol. 189, 4426–4436 (2012).
24. Jiménez, B. et al. Signals leading to apoptosis-dependent inhibition
of neovascularization by thrombospondin-1. Nat. Med. 6,
41–48 (2000).
25. Volpert, O. V. et al. Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and
pigment epithelium-derived factor. Nat. Med. 8, 349–357 (2002).
26. Lamy, L. et al. Interactions between CD47 and thrombospondin
reduce inflammation. J. Immunol. 178, 5930–5939 (2007).
27. Ribeiro, S. M., Poczatek, M., Schultz-Cherry, S., Villain, M. & MurphyUllrich, J. E. The activation sequence of thrombospondin-1 interacts
with the latency-associated peptide to regulate activation of latent
transforming growth factor-beta. J. Biol. Chem. 274,
13586–13593 (1999).
28. Schultz-Cherry, S. et al. Regulation of transforming growth factorbeta activation by discrete sequences of thrombospondin 1. J. Biol.
Chem. 270, 7304–7310 (1995).
29. Ma, X. et al. CD36-mediated ferroptosis dampens intratumoral CD8.
Cell Metab. 33, 1001–1012.e1005 (2021).
30. Lee, H. O. et al. Lineage-dependent gene expression programs
influence the immune landscape of colorectal cancer. Nat. Genet.
52, 594–603 (2020).
31. Zhang, L. et al. Single-cell analyses inform mechanisms of myeloidtargeted therapies in colon cancer. Cell 181, 442–459.e429 (2020).
32. Ma, J., Sun, X., Wang, Y., Chen, B. & Qian, L. Fibroblast-derived
CXCL12 regulates PTEN expression and is associated with the proliferation and invasion of colon cancer cells via PI3k/Akt signaling.
Cell Commun. Signal. 17, 119 (2019).
33. Khaliq, A. M. et al. Refining colorectal cancer classification and
clinical stratification through a single-cell atlas. Genome Biol. 23,
113 (2022).
34. Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
35. Daubon, T. et al. Deciphering the complex role of thrombospondin1 in glioblastoma development. Nat. Commun. 10, 1146 (2019).
36. Saadi, A. et al. Stromal genes discriminate preinvasive from invasive
disease, predict outcome, and highlight inflammatory pathways in
digestive cancers. Proc. Natl Acad. Sci. USA 107, 2177–2182 (2010).
37. Hoshino, A. et al. Extracellular vesicle and particle biomarkers
define multiple human cancers. Cell 182, 1044–1061.e1018 (2020).
38. Cao, L. et al. Proteogenomic characterization of pancreatic ductal
adenocarcinoma. Cell 184, 5031–5052.e5026 (2021).
39. Yang, H., Zhou, T., Sorenson, C. M., Sheibani, N. & Liu, B. MyeloidDerived TSP1 (Thrombospondin-1) contributes to abdominal aortic
aneurysm through suppressing tissue inhibitor of
metalloproteinases-1. Arterioscler. Thromb. Vasc. Biol. 40,
e350–e366 (2020).
40. Memetimin, H. et al. Myeloid-specific deletion of thrombospondin 1
protects against inflammation and insulin resistance in long-term
diet-induced obese male mice. Am. J. Physiol. Endocrinol. Metab.
315, E1194–E1203 (2018).
41. Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as
regulators of the immune system. Nat. Rev. Immunol. 9,
162–174 (2009).
42. Condamine, T., Ramachandran, I., Youn, J. I. & Gabrilovich, D. I.
Regulation of tumor metastasis by myeloid-derived suppressor
cells. Annu. Rev. Med. 66, 97–110 (2015).
43. Gubin, M. M. et al. High-dimensional analysis delineates myeloid and
lymphoid compartment remodeling during successful immunecheckpoint cancer therapy. Cell 175, 1014–1030.e1019 (2018).
Nature Communications | (2023)14:5534
https://doi.org/10.1038/s41467-023-41095-y
44. Zhu, Y. et al. Tissue-resident macrophages in pancreatic ductal
adenocarcinoma originate from embryonic hematopoiesis and
promote tumor progression. Immunity 47, 323–338.e326
(2017).
45. Dawson, D. W. et al. CD36 mediates the In vitro inhibitory effects of
thrombospondin-1 on endothelial cells. J. Cell Biol. 138,
707–717 (1997).
46. Bagavandoss, P. & Wilks, J. W. Specific inhibition of endothelial cell
proliferation by thrombospondin. Biochem. Biophys. Res. Commun.
170, 867–872 (1990).
47. Saito, Y. et al. SIRPα. Proc. Natl Acad. Sci. USA 114,
E10151–E10160 (2017).
48. Bankhead, P. et al. QuPath: open source software for digital
pathology image analysis. Sci. Rep. 7, 16878 (2017).
49. Robinson, S. M. et al. Pathogenesis of FOLFOX induced sinusoidal
obstruction syndrome in a murine chemotherapy model. J. Hepatol.
59, 318–326 (2013).
50. Schindelin, J. et al. Fiji: an open-source platform for biologicalimage analysis. Nat. Methods 9, 676–682 (2012).
51. Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell
184, 3573–3587.e3529 (2021).
52. Hafemeister, C. & Satija, R. Normalization and variance stabilization
of single-cell RNA-seq data using regularized negative binomial
regression. Genome Biol. 20, 296 (2019).
53. Eide, P. W., Bruun, J., Lothe, R. A. & Sveen, A. CMScaller: an R
package for consensus molecular subtyping of colorectal cancer
pre-clinical models. Sci. Rep. 7, 16618 (2017).
54. Niu, B. et al. MSIsensor: microsatellite instability detection using
paired tumor-normal sequence data. Bioinformatics 30,
1015–1016 (2014).
Acknowledgements
Research was supported by the Project for Cancer Research and
Therapeutic Evolution (P-CREATE, 18cm0106142h0001 (A.F.),
20cm0106177h0001 (H.S.), 20cm0106375h0001 (A.F.),
21cm0106283h0001 (Y.N.)), P-PROMOTE (22cm0106283h0002 (Y.N.),
22ama221515h0001 (H.S.)), and PRIME (20gm6010022h0003 (A.F.))
from the Japan Agency for Medical Research and Development (AMED);
the Fusion Oriented Research for disruptive Science and Technology
(FOREST, 23719768 (Y.N.)); Moonshot Research and Development Program (JPMJMS2022-1), and COI-NEXT (JPMJPF2018); the JSPS KAKENHI
(JP19H03639 (A.F.), JP20K22841 (Y.H.), JP20H03659 (H.S.), JP21K19480
(H.S.), and JP21H02902 (Y.N.)); the foundations of Takeda Science (Y.N.),
Princess Takamatsu Cancer Research (Y.N.), Astellas, Daiichi Sankyo of
Life Science (Y.N.); JST SPRING (JPMJSP2110 (M.O.)). We thank Mason
Freeman (Harvard Medical School) for providing CD36-/- mice and
Toshiko Sato for technical assistance. A part of this study was conducted
through the CORE Program of the Radiation Biology Center, Kyoto
University.
Author contributions
M.O. and Y.N. coordinated the project and designed the experiments
with help from K.Mi., M.K., G.Y., Mi.N., K.H., Y.F., M.S., T.Mas., O.A.,
Mu.N., T.Y., Sa.O., Y.H., M.T. and A.F. M.O., K.I. and T.Mar. performed the
experiments with help from A.H., T.K. and K.Kab. N.Ao. analyzed TMA
data with help from Q.H. and A.M-O. N.Ag., T.U., H.K., K.Kaw., M.Y.,
K.Ma., Y.S., T.Mat., K.O., and N.S. provided materials that made the study
possible. M.O. and K.I. performed scRNA-seq with help from N.K.,
M.M.N. and Se.O. M.O., K.I. and Y.N. analyzed the data with help from
Y.M. and A.D. M.O and Y.N. wrote the manuscript with help from A.F.,
M.T-M., J.M. and H.S.
Competing interests
Yuichi Fukunaga is employed by Sumitomo Pharma Co., Ltd. The
remaining authors disclose no conflicts.
18
Article
Additional information
Supplementary information The online version contains
supplementary material available at
https://doi.org/10.1038/s41467-023-41095-y.
Correspondence and requests for materials should be addressed to
Yuki Nakanishi.
Peer review information Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work.
A peer review file is available.
Reprints and permissions information is available at
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https://doi.org/10.1038/s41467-023-41095-y
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© The Author(s) 2023
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Mayuki Omatsu1, Yuki Nakanishi 1 , Kosuke Iwane1, Naoki Aoyama1, Angeles Duran2, Yu Muta 2,12,
Anxo Martinez-Ordoñez2, Qixiu Han2, Nobukazu Agatsuma1, Kenta Mizukoshi1, Munenori Kawai1, Go Yamakawa1,
Mio Namikawa1, Kensuke Hamada1, Yuichi Fukunaga1,3, Takahiro Utsumi1, Makoto Sono1, Tomonori Masuda 1,
Akitaka Hata4, Osamu Araki1, Munemasa Nagao 1, Takaaki Yoshikawa1, Satoshi Ogawa 1, Yukiko Hiramatsu 1,
Motoyuki Tsuda1, Takahisa Maruno1, Toshiaki Kogame4, Hiroaki Kasashima 5, Nobuyuki Kakiuchi 1,6,
Masahiro M. Nakagawa 7, Kenji Kawada 8, Masakazu Yashiro5, Kiyoshi Maeda5, Yasuyuki Saito 9,
Takashi Matozaki 9,10, Akihisa Fukuda1, Kenji Kabashima 4, Kazutaka Obama8, Seishi Ogawa7, Nader Sheibani
Maria T. Diaz-Meco 2, Jorge Moscat 2 & Hiroshi Seno1
11
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. 2Department of Pathology and Laboratory
Medicine, Weill Cornell Medicine, New York, USA. 3Cancer Research Unit, Sumitomo Pharma Co., Ltd, Osaka, Japan. 4Department of Dermatology, Kyoto
University Graduate School of Medicine, Kyoto, Japan. 5Department of Gastroenterological Surgery, Osaka Metropolitan University, Osaka, Japan. 6The
Hakubi Center for Advanced Research, Kyoto University, Kyoto, Japan. 7Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
Department of Gastrointestinal Surgery, Kyoto University, Graduate School of Medicine, Kyoto, Japan. 9Division of Molecular and Cellular Signaling,
Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan. 10Division of Biosignal Regulation, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan. 11Department of Ophthalmology and Visual
Sciences, University of Wisconsin-, Madison, Wisconsin, USA. 12Present address: Department of Gastroenterology and Hepatology, Kyoto University Graduate
School of Medicine, Kyoto, Japan.
e-mail: yuki@kuhp.kyoto-u.ac.jp
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