Understanding how obesity-induced tumour metabolites drive prostate cancer progression

This study aims to show that changing diet can reverse obesity-induced tumour and prostate cancer progression

  • Topic: Prostate cancer
  • Institution: Italian National Council of Research
  • Country: Italy
  • Status: Ongoing
Researcher: Giorgia Zadra

Integrating tissue-based spatial information to elucidate how obesity- induced tumour metabolites drive prostate cancer progression


Obesity is increasing at alarming rates in the western countries. For men, being obese is associated with greater risk of severe, treatment-resistant prostate cancer (PCa) and death. Hence, there is an urgent need to better understand and halt the mechanisms driving aggressiveness in obesity-associated PCa and improve patient survival.

Our data in mice demonstrated that obesity alters the way PCa cells process sugars, resulting in the accumulation of a metabolic product called lactate. Tumours from obese mice are not only more aggressive but also further accumulate lactate, which is ultimately secreted into the surrounding tumour microenvironment (TME).

The latter is populated by cells that promote tumour growth and cells of the immune system that act as either tumour friend or foe. Thus, understanding how metabolites create a milieu permissive for disease progression is crucial to developing new therapeutic strategies.

Aims and Objectives

This study aims to:

  1. Demonstrate that obesity-induced lactate accumulation blunts tumour immunosurveillance and favours PCa progression, which can be reversed by dietary intervention or lactate blockade
  2. Investigate lactate accumulation in obese patients, and define whether it is associated with impaired anti-tumour immunity, worse prognosis, and therapy resistance
  3. Test whether
    a) lactate accumulation blockade improves the efficacy of current hormonal treatments and experimental therapies promoting anti-tumour immunity and whether
    b) pre-treatment assessment of lactate levels can predict therapy response.

How it will be done

We will perform a comprehensive characterization of the prostate TME using cutting-edge technologies that provide information on the quantity and localization of metabolites, oncogenic markers/pathways, and immune cell populations directly in the tumour tissue.

This will be done in PCa tissues from ad hoc mouse models recapitulating aggressive human PCa in which obesity and obesity reversal is achieved by diet modulation and in post-surgery specimens from PCa patients with known obesity status.

These data will be integrated with patient clinical information to define whether lactate levels are predictive markers of prognosis and therapy response.

Both mouse models and ex-vivo tumour explants from PCa patients will be further used to rapidly evaluate whether drugs inhibiting lactate accumulation can improve the efficacy of hormonal or immune therapies.

Potential impact

This study will improve our current understanding of the deleterious effects of obesity on PCa progression by directly connecting obesity-associated dysregulation of tumour metabolites, specifically lactate, with the impairment of anti-tumour immunity and the acquisition of tumour features permissive for metastatic spread.

Since lactate can be modulated through dietary and pharmacological approaches, this study not only will put forward new tailored approaches to improve hormonal and immune therapies (so far disappointing) but will also support dietary intervention as adjunct to standard of care in PCa.

Finally, this study will clarify whether measuring lactate may help identifying patients at high risk of deadly disease and in need for more effective combinatorial treatments.

As lactate can be safely measured in the clinic and drugs targeting lactate are in development, the outcomes of our study will contribute to improved management of aggressive PCa and therapeutic decision-making.

Metabolites are key modulators of cell signaling, gene expression, and tumour immune surveillance. We will explore metabolites and metabolic pathways in a spatial dimension, gain new insights on the metabolic crosstalk between prostate cancer cells and tumour immune microenvironment in the context of obesity, and understand how metabolites promote disease progression towards castration resistance. This study will improve our current understanding of the link between obesity and advanced prostate cancer and support the development of new therapeutic modalities against castration-resistant prostate cancer.
Dr Giorgia Zadra