Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells

Cañellas-Socias, Adrià; Cortina, Carme; Hernando‐Momblona, Xavier; Palomo-Ponce, Sergio; Mulholland, Eoghan J.; Turón, Gemma; Mateo, Lídia; Conti, Sefora; Roman, Olga; Sevillano, Marta; Slebe, Felipe; Stork, Diana; Caballé, Adrià; Berenguer‐Llergo, Antoni; Álvarez-Varela, Adrián; Fenderico, Nicola; Novellasdemunt, Laura; Jiménez-Gracia, Laura; Sipka, Tamara; Bardia, Lídia; Lorden, Patricia; Colombelli, Julien; Heyn, Holger; Trepat, Xavier; Tejpar, Sabine; Sancho, Elena; Tauriello, Daniele V.F.; Leedham, Simon J.; Attolini, Camille Stephan‐Otto; Batlle, Eduard

doi:10.1038/s41586-022-05402-9

Cited by 64 publications

(32 citation statements)

References 86 publications

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“…MTOs were previously derived from primary tumors arising in genetically engineered mouse models with compound genetic alterations ( Apc , Kras , Trp53 , Tgfbr2 ) 17 . For bioluminescence tracking, MTOs were infected with a lentivirus encoding an eGFP–firefly luciferase fusion reporter construct under the control of the Pgk1 promoter 73 . For culture expansion, MTOs were embedded in basement-membrane extract (BME) medium (Cultrex BME Type 2, Amsbio) and cultured at 37 °C with 85–90% humidity, atmospheric O 2 and 5% CO 2 in advanced DMEM/F12 supplemented with 10 mM HEPES, Glutamax, B-27 without retinoid acid (all Life Technologies), 100 ng/ml recombinant NOGGIN and 50 ng/ml recombinant EGF (Peprotech).…”

Section: Methodsmentioning

confidence: 99%

Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy

et al. 2023

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A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased. We determine that CT accumulation in CAFs intensifies TGF-beta activity, leading to the production of multiple factors enhancing cancer aggressiveness. We establish periostin as a stromal marker of chemotherapeutic activity intrinsically upregulated in consensus molecular subtype 4 (CMS4) tumors and highly expressed before and/or after treatment in patients unresponsive to therapy. Collectively, our study underscores the ability of CT-retaining CAFs to support cancer progression and resistance to treatment.

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Section: Methodsmentioning

confidence: 99%

Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy

et al. 2023

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“…Lastly, marker genes related to regeneration (ANXA1) and metastatic relapse (EMP1) were enriched in TINCs (Fig. 3m) 24,25 . We conclude that RNF43 mutations facilitate tumour cell differentiation into niche factor-producing cells, which explains the acquired niche-independent growth state of these tumours.…”

Section: Mainmentioning

confidence: 99%

RNF43 mutations facilitate colorectal cancer metastasis via formation of a tumour-intrinsic niche

Bugter

Bouazzaoui

Küçükköse

et al. 2022

Preprint

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Colorectal cancer (CRC) develops via two mutually exclusive genetic pathways that involve distinct WNT pathway alterations. Downstream APC mutations initiate development of conventional WNT-high adenocarcinomas. By contrast, RNF43 mutations induce hypersensitivity to WNTs at the receptor level and are mainly found in BRAF V600E-initiated serrated adenomas that advance into WNT-low mucinous adenocarcinomas with poor prognosis upon metastasis. How RNF43 mutations contribute to tumour progression remains unclear. Here, we employed gene editing to repair RNF43 mutations in patient-derived CRC organoids. In comparison to their RNF43-mutant counterparts, RNF43-corrected CRC organoids display a diminished mucinous phenotype, loss of niche factor independency and loss of metastatic capacity upon orthotopic transplantation in mice. Mechanistically, mutant RNF43 promotes formation of a non-dividing secretory cell population that secretes essential growth factors and provide a state of self-sufficiency to the cancer epithelium. Unlike APC mutations, we show that RNF43-mutations provide tuneable WNT levels that permits the formation of these niche-like cells in parallel to proliferative WNT-high cancer cells. Also in patient samples, formation of these tumour-intrinsic niche cells (TINCs) correlate with RNF43-mutant CRC, mucinous histology and metastatic capacity and represents a cellular mechanism by which tumours acquire self-sufficiency.

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“…Cañellas-Socias et al. 1 recently published an inspiring article in Nature that focuses on the identification and characterization of the residual tumor cells responsible for CRC relapse. First, in this study, from a large transcriptomic cohort of patients with CRC, they were able to determine a set of genes associated with poor prognosis; 99 of these recurrence-associated genes were found to be upregulated in the tumor epithelial cells, named as epithelial-specific high-risk gene set (EpiHR).…”

Section: Metastatic Recurrence In Colorectal Cancer Arises From Resid...mentioning

confidence: 99%

In the Literature: January 2023

Martín-Arana¹,

Gambardella²,

Tarazona³

et al. 2023

ESMO Open

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Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells

Cited by 64 publications

References 86 publications

Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy

Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy

RNF43 mutations facilitate colorectal cancer metastasis via formation of a tumour-intrinsic niche

In the Literature: January 2023

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