2. Academic Validation
  3. Clonal cooperation through soluble metabolite exchange facilitates metastatic outgrowth by modulating Allee effect

Clonal cooperation through soluble metabolite exchange facilitates metastatic outgrowth by modulating Allee effect

  • Sci Adv. 2023 Sep 15;9(37):eadh4184. doi: 10.1126/sciadv.adh4184.
Benjamin J Hershey 1,  Sara Barozzi 1,  Fabrizio Orsenigo 1,  Simone Pompei 1,  Fabio Iannelli 1,  Stephan Kamrad 2,  Vittoria Matafora 1,  Federica Pisati 3,  Ludovico Calabrese 1,  Giuseppe Fragale 1,  Giulia Salvadori 1,  Emanuele Martini 1,  Maria Grazia Totaro 1,  Serena Magni 1,  Rui Guan 2,  Dario Parazzoli 1,  Paolo Maiuri 4,  Angela Bachi 1,  Kiran R Patil 2,  Marco Cosentino Lagomarsino 1 5,  Kristina M Havas 1
Affiliations

Affiliations

  • 1 IFOM ETS The AIRC Institute of Molecular Oncology, Milan, Italy.
  • 2 Medical Research Council Toxicology Unit, Cambridge, UK.
  • 3 Histopathology Unit, Cogentech S.C.A.R.L., Milan, Italy.
  • 4 University of Naples Federico II, Naples, Italy.
  • 5 University of Milano, Milan, Italy.
PMID: 37713487 DOI: 10.1126/sciadv.adh4184
Abstract

Cancers feature substantial intratumoral heterogeneity of genetic and phenotypically distinct lineages. Although interactions between coexisting lineages are emerging as a potential contributor to tumor evolution, the extent and nature of these interactions remain largely unknown. We postulated that tumors develop ecological interactions that sustain diversity and facilitate metastasis. Using a combination of fluorescent barcoding, mathematical modeling, metabolic analysis, and in vivo models, we show that the Allee effect, i.e., growth dependency on population size, is a feature of tumor lineages and that cooperative ecological interactions between lineages alleviate the Allee barriers to growth in a model of triple-negative breast Cancer. Soluble metabolite exchange formed the basis for these cooperative interactions and catalyzed the establishment of a polyclonal community that displayed enhanced metastatic dissemination and outgrowth in xenograft models. Our results highlight interclonal metabolite exchange as a key modulator of tumor ecology and a contributing factor to overcoming Allee effect-associated growth barriers to metastasis.

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