Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion

  1. Gerard Cantero-Recasens  Is a corresponding author
  2. Josune Alonso-Marañón
  3. Teresa Lobo-Jarne
  4. Marta Garrido
  5. Mar Iglesias
  6. Lluis Espinosa  Is a corresponding author
  7. Vivek Malhotra  Is a corresponding author
  1. Vall d'Hebron Institut de Recerca, Spain
  2. Institut Mar d'Investigacions Mèdiques, Spain
  3. The Barcelona Institute of Science and Technology, Spain

Abstract

15% of colorectal cancers (CRC) cells exhibit a mucin hypersecretory phenotype, which is suggested to provide resistance to immune surveillance and chemotherapy. We now formally show that colorectal cancer cells build a barrier to chemotherapeutics by increasing mucins' secretion. We show that low levels of KChIP3, a negative regulator of mucin secretion (Cantero-Recasens et al., 2018), is a risk factor for CRC patients' relapse in subset of untreated tumours. Our results also reveal that cells depleted of KChIP3 are four times more resistant (measured as cell viability and DNA damage) to chemotherapeutics 5-Fluorouracil plus Irinotecan (5-FU+iri.) compared to control cells, whereas KChIP3 overexpressing cells are 10 times more sensitive to killing by chemotherapeutics. Similar increase in tumour cell death is observed upon chemical inhibition of mucin secretion by the sodium/calcium exchanger (NCX) blockers (Mitrovic et al., 2013). Finally, sensitivity of CRC patient-derived organoids to 5-FU+iri increases 40-fold upon mucin secretion inhibition. Reducing mucin secretion thus provides a means to control chemoresistance of mucinous colorectal cancer cells and other mucinous tumours.

Data availability

All data generated or analysed are included in the manuscript

The following previously published data sets were used

Article and author information

Author details

  1. Gerard Cantero-Recasens

    Renal Physiopathology Group, Vall d'Hebron Institut de Recerca, Barcelona, Spain
    For correspondence
    gerard.cantero@vhir.org
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6452-782X
  2. Josune Alonso-Marañón

    Cancer Research Program, Institut Mar d'Investigacions Mèdiques, Barcelona, Spain
    Competing interests
    No competing interests declared.
  3. Teresa Lobo-Jarne

    Cancer Research Program, Institut Mar d'Investigacions Mèdiques, Barcelona, Spain
    Competing interests
    No competing interests declared.
  4. Marta Garrido

    Cancer Research Program, Institut Mar d'Investigacions Mèdiques, Barcelona, Spain
    Competing interests
    No competing interests declared.
  5. Mar Iglesias

    Department of Pathology, Institut Mar d'Investigacions Mèdiques, Barcelona, Spain
    Competing interests
    No competing interests declared.
  6. Lluis Espinosa

    Cancer Research Program, Institut Mar d'Investigacions Mèdiques, Barcelona, Spain
    For correspondence
    lespinosa@imim.es
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2897-4099
  7. Vivek Malhotra

    Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
    For correspondence
    vivek.malhotra@crg.eu
    Competing interests
    Vivek Malhotra, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6198-7943

Funding

Ministerio de Economía, Industria y Competitividad, Gobierno de España (BFU2013-44188-P)

  • Vivek Malhotra

Instituto de Salud Carlos III (PI19-00013)

  • Lluis Espinosa

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2022, Cantero-Recasens et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,664
    views
  • 358
    downloads
  • 10
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Gerard Cantero-Recasens
  2. Josune Alonso-Marañón
  3. Teresa Lobo-Jarne
  4. Marta Garrido
  5. Mar Iglesias
  6. Lluis Espinosa
  7. Vivek Malhotra
(2022)
Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion
eLife 11:e73926.
https://doi.org/10.7554/eLife.73926

Share this article

https://doi.org/10.7554/eLife.73926

Further reading

    1. Cell Biology
    Kaili Du, Hongyu Chen ... Dan Li
    Research Article

    Niemann–Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.

    1. Cell Biology
    Yan Song, Linda J Fothergill ... Gene W Yeo
    Research Article

    Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine to mediate disparate physiological responses. However, the molecular and cellular basis for functional diversity of ECs remains to be adequately defined. Here, we integrated single-cell transcriptomics with spatial image analysis to identify 14 EC clusters that are topographically organized along the gut. Subtypes predicted to be sensitive to the chemical environment and mechanical forces were identified that express distinct transcription factors and hormones. A Piezo2+ population in the distal colon was endowed with a distinctive neuronal signature. Using a combination of genetic, chemogenetic, and pharmacological approaches, we demonstrated Piezo2+ ECs are required for normal colon motility. Our study constructs a molecular map for ECs and offers a framework for deconvoluting EC cells with pleiotropic functions.