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Hold it or let it go: a niche decision on cancer growth

Periodic Reporting for period 5 - WHOLENICHE (Hold it or let it go: a niche decision on cancer growth)

Okres sprawozdawczy: 2022-10-01 do 2023-09-30

The synergistic cooperation between tumour cells and their associated host causes their co-evolution leading to cancer progression. This co-operation is fundamental, and it regulates all the aspect of tumour progression as well as drug sensitivity.
The question we ask with this project is to understand the key perturbations in the normal cell compartment of the tissue induced by cancer cells during primary tumour or metastasis onset. This project focuses on the dissection of the local tissue microenvironment during primary tumour initiation, metastatic growth, and latency to the bone, but also on the impact of the cancer dependent systemic changes in neutrophils influencing metastatic efficiency.
Addressing those fundamental question will not only have benefit to improve the treatment for cancers, but also help understanding what increase cancer susceptibility and therefore cancer prevention.
The overall objective of the project is the identify signals and processes that can be targeted in the interaction between cancer cells and normal tissue cells. Targeting those interaction will predispose cancer to respond better to standard treatment and reduce chances of relapses and metastatic recurrence.
The wok was organized in the following part and over the period of the grant has produced the achievement described below:

WP1.1 The work under this working package has progressed extremely well. We have reached our target and set up our niche labelling tool, we have used it to perfum a study that have discover the presence of alveolar cells in the metastatic niche of pulmonary metastasis from breast cancer cells. This finding revised the canonical concept that tissue cells responding to cancer are only derived from the stromal compartment of the tissue and identify epithelial cells as a very early niche component. Here we have also reported the activation of stemness program in this niche epithelial cells Ombrato et al., Nature 2019.
We have continued this work with a follow up project currently under revision (available here: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4540765). Here we characterise the stemness program activated in different niches of metastatic cells of different tumour types. We provide evidence for a process whereby lung stem-cell line in the niche increases the tumorigenic potential of the metastatic cells in a process we termed “reflected stem stemness” (Rodrigues et al., Trends Cell Biol. 2022).

W1.2 We had few initial issues with the generation of this animal model, so this WP has progressed slower than initially estimated.
In the meantime, we have address questions about the matching required by the tumorigenic niches for primary tumour growth. We have discovered that when the intrinsic characteristics of cancer cells are perturbed, there is perturbation in the initiation of the tumorigenic niche, which compromises aggressive long term growth. This work was published in 2022 (Perdrix Rosell et al., Cancer Lett. 2022).
Despite the initial difficulties, we have generated the mouse model using the labelling system in two different backgrounds.

WP1.3. Project around neutrophils biology and plasticity have progress well in the lab.
In a first study we have looked at the effect of neutrophils on lung cancer initiation upon chemically induction. This work highlighted that lung neutrophils, can amplify the genotoxic effect of Urethane, a toxic chemical contained in tabacco smoke. In this way, the presence of neutrophils increases the susceptibility of the tissue to lung cancer initiation. However, this activity is restricted to the moment of exposure and neutrophils do not acquire a long-lasting DNA damage activity. This work was published in 2020 (Wculek et al., iScience 2020).
In a second project have performed a study looking at neutrophils plasticity in responses of radiotherapy, one of the most common cancer therapies used. We have performed a study that linked this neutrophils activation in response to lung radiation injury to their ability to support healthy tissue regeneration. The neutrophils-dependent regenerative environment, strongly favour metastatic initiation and growth. This work was published in 2022 (Nolan et al., Nature Cancer 2022).
I have also contributed to the broader field of neutrophils biology by writing several reviews on the topic: Hedrick CC and Malanchi I. “Neutrophils in cancer: heterogeneous and multifaceted.” Nat Rev Immunol. 2022; Quail DFet al., “Neutrophil phenotypes and functions in cancer: A consensus statement.” J Exp Med. 2022. Nolan E and Malanchi I. “Connecting the dots: Neutrophils at the interface of tissue regeneration and cancer.” Semin Immunol. 2021.

Lastly, under this WP, we have performed a study characterising the changes in cancer-primed neutrophils. This project in currently pursued in the lab and have generated valuable preliminary data.
On a similar line we have perform a first proof of concept study showing that circulating neutrophil’s kinase activations are specifically perturbed in early stage of breast cancer patients (Ramassur et al., Breast Cancer Res, 2023). This could lead to the design of novel biomarkers helping to detect cancer at early stages.

WP2 We have refine the development and characterization of the Extramedullary (EM) bone system. We have implemented this system to study both:
1. Spontaneous dissemination to the bone of cancer cells from primary tumours to study what are the bone environment conditions influencing seeding and persistence of DTCs in the bone.
2. Establishment of metastatic competent cells to remain dormant cells within the EM bone.
Using this new system, we have produced a study showing that metastatic reactivation in the bone does not necessary occur via sadden switch in cancer cells behaviour, but rather needs multiple waves of emergency granulopoiesis activations to push cells toward an increased chance of metastatic growth. This work is currently under revision and available in Research Square (https://europepmc.org/article/ppr/ppr697870).
The results of this project push the field beyond the state of the art by:
• Discovering novel interactions between metastatic cells in the lung and parenchymal cells and highlight the idea of the activation of a local stem cell program as hallmark of the metastatic niche.
• Provided the cancer field with and additional tool to study cancer-host interactions in vivo.
• Revealed a new pro-metastatic activity of neutrophils linked to their previously underestimated pro-regenerative functions.
• We also provide evidence of circulating neutrophil’s early perturbation in breast cancer patients, that could lead to the development of potential biomarker to detect early disease.
• Provide evidence of an alternative model for metastatic dormancy reactivation alternative to a sadden switch: where dormant cells persist in the tissue and gradually increase chance of outgrowth by subsequent inflammatory stimuli causing emergency granulopoiesis.
Metastatic cells interaction with innate immuno cells