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. 2025 Aug 20.
doi: 10.1245/s10434-025-18039-5. Online ahead of print.

SPARC Induces COL1A1/COL3A1 Expressions Representing Aggressive Molecular Cancer-Associated Fibroblasts Signatures and CSF1-Mediated Cancer Invasion in Colorectal Cancer

Yusuke Nie #  1 , Yoshiki Fujiyama #  1 , Shumpei Shibaki  1 , Riku Okamoto  1 , Kota Okuno  1 , Keiko Oki  1 , Akiko Watanabe  1 , Yu Kuroda  1 , Takuya Goto  1 , Kazuko Yokota  1 , Keita Kojima  1 , Hiroki Harada  1 , Mikiko Kidachi  1 , Takafumi Soeno  1 , Mitsuo Yokota  1 , Takeshi Kaida  1 , Shuji Nakamoto  1 , Nobuyuki Nishizawa  2 , Hidefumi Kubo  2 , Hiroshi Tajima  2 , Takashi Kaizu  2 , Takahiro Yamanashi  3 , Masaki Nakamura  4   5   6   7 , Hidero Kitasato  4   5   6   7 , Tsutomu Yoshida  8 , Yoshiki Murakumo  8 , Makoto Saegusa  8 , Takafumi Sangai  9 , Naoki Hiki  10 , Takeshi Naitoh  3 , Yusuke Kumamoto  2 , Keishi Yamashita  11
Affiliations

SPARC Induces COL1A1/COL3A1 Expressions Representing Aggressive Molecular Cancer-Associated Fibroblasts Signatures and CSF1-Mediated Cancer Invasion in Colorectal Cancer

Yusuke Nie et al. Ann Surg Oncol. .

Abstract

Background: Secreted protein, acidic and rich in cysteine (SPARC) may play an important role in tumor microenvironment (TME) contribution to metastasis, however molecular mechanism of SPARC contribution to TME remains elusive.

Experimental design: In this study, SPARC molecular status was explored for its clinical and functional relevance to metastasis in the context of its stromal overexpression, which may represent colorectal cancer (CRC) progression.

Results: SPARC expression was highly specific to cancer stroma of CRC tumors (GSE35608) and exhibited prognostic relevance. SPARC knockdown (KD) in cancer-associated fibroblasts (CAFs) resulted in diminished metastatic phenotypes, accompanied by robust suppression of COL1A1/COL3A1 expressions and multiple secretome genes. Among the secretome genes, CSF1 was closely associated with stromal SPARC expression, and it was demonstrated that the CSF1/CSF1R axis was required for SPARC-induced cancer invasion. Comprehensive selection by stromal specificity and its SPARC association identified CAF-associated genes (CAFGs), including classical CAFs markers and COL family genes, which were uniquely enriched as higher priority for prognosis. These findings suggest that SPARC-mediated induction of COL family genes and secretome in the TME may be primarily featured against the host rather than be protective.

Conclusions: Our present findings may aid in simplifying molecular understanding of aggressive TME and enrich bona-fide therapeutic targets for cancer metastasis.

Keywords: Cancer metastasis; Cytokine; Interferon; Prognosis; SPARC.

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Conflict of interest statement

Disclosure: Takeshi Naitoh has received honoraria from Chugai Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, Eli Lilly Japan, and Daiichi Sankyo. Yusuke Nie, Yoshiki Fujiyama, Shumpei Shibaki, Riku Okamoto, Kota Okuno, Keiko Oki, Akiko Watanabe, Yu Kuroda, Takuya Goto, Kazuko Yokota, Keita Kojima, Hiroki Harada, Mikiko Kidachi, Takafumi Soeno, Mitsuo Yokota, Takeshi Kaida, Shuji Nakamoto, Nobuyuki Nishizawa, Hidefumi Kubo, Hiroshi Tajima, Takashi Kaizu, Takahiro Yamanashi, Masaki Nakamura, Hidero Kitasato, Tsutomu Yoshida, Yoshiki Murakumo, Makoto Saegusa, Takafumi Sangai, Naoki Hiki, Yusuke Kumamoto, and Keishi Yamashita have no disclosures to declare that may be relevant to the contents of this study.

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