2. Academic Validation
  3. Divergent Evolution of Malignant Subclones Maintains a Balance Between Induced Aggressiveness and Intrinsic Drug Resistance in T Cell Cancer

Divergent Evolution of Malignant Subclones Maintains a Balance Between Induced Aggressiveness and Intrinsic Drug Resistance in T Cell Cancer

  • Cancer Discov. 2025 Jun 16. doi: 10.1158/2159-8290.CD-24-1856.
Terkild B Buus 1,  Chella Krishna Vadivel 1,  Maria Gluud 1,  Martin R J Namini 1,  Ziao Zeng 1,  Signe Hedebo 2,  Menghong Yin 3,  Andreas Willerslev-Olsen 1,  Emil M H Pallesen 1,  Lang Yan 1,  Edda P Blümel 1,  Emma U Ewing 1,  Sana Ahmad 1,  Lara P Sorrosal 1,  Carsten Geisler 1,  Charlotte M Bonefeld 1,  Anders Woetmann 1,  Mads H Andersen 4,  Tomas Mustelin 5,  Claus Johansen 6,  Marion Wobser 7,  Maria R Kamstrup 8,  Emmanuella Guenova 9,  Jürgen C Becker 10,  Sergei B Koralov 11,  Rikke Bech 12,  Niels Ødum 1
Affiliations

Affiliations

  • 1 University of Copenhagen, Copenhagen, Denmark.
  • 2 Aarhus University Hospital, Aarhus N, Denmark.
  • 3 University of Duisburg-Essen, Germany.
  • 4 Herlev Hospital, Herlev, Denmark.
  • 5 University of Washington, Seattle, WA, United States.
  • 6 Aarhus University Hospital, Aarhus, Denmark.
  • 7 University Hospital Wuerzburg, Wuerzburg, Germany.
  • 8 bispebjerg hospital, Copenhagen, Denmark.
  • 9 Johannes Kepler University, Linz, Austria, Linz, Austria.
  • 10 German Cancer Research Center, Essen, Germany.
  • 11 New York University, New York, NY, United States.
  • 12 Aarhus University Hospital, Denmark.
PMID: 40516109 DOI: 10.1158/2159-8290.CD-24-1856
Abstract

Evolution and outgrowth of drug-resistant Cancer cells is a common cause of treatment failure. Patients with leukemic cutaneous T-cell lymphoma (L-CTCL) have a poor prognosis due to development of drug-resistance and severe Bacterial infections. Here, we show that most L-CTCL patients harbor multiple genetically distinct subclones that express an identical clonal antigen receptor but display distinct phenotypes and functional properties. These co-existing malignant subclones exhibit differences in tissue homing, metabolism, and cytokine expression, and respond differently to extrinsic factors like Staphylococcus (S.)aureus and Cancer drugs. Indeed, while S. aureus toxins selectively enhance activation and proliferation of certain subclones, these responsive subclones are also the most intrinsically sensitive to Cancer drugs when the stimuli are removed. Consequently, although divergent evolution of malignant subclones drives aggressiveness, adaptability and drug-resistance, by removing extrinsic stimuli and mapping malignant subclones, we can expose inherent vulnerabilities that can be exploited in the treatment of these cancers.

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